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marrow transplantation: diagnosis at autopsy. Transpl Infect Dis 2008: 10: 372^374. All rights reserved. Abstract:Toxoplasmosis is a rare but well recognized ...
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Toxoplasmosis with hemophagocytic syndrome after bone marrow transplantation: diagnosis at autopsy

Abstract: Toxoplasmosis is a rare but well recognized opportunistic infection that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Besides encephalitis, other common presentations of Toxoplasma gondii infection are interstitial pneumonitis and myocarditis. Because of its non-speci¢c clinical and biological signs and its lethal outcome, toxoplasmosis is often misdiagnosed and only revealed at autopsy.We report a case of a postmortem diagnosis of disseminated toxoplasmosis associated with hemophagocytic syndrome, which underlines the value of necropsy in cases of death after transplantation.We also discuss clinical presentations and risk factors that lead to toxoplasmosis in allo-HSCT recipients. S. Duband, J. Cornillon, E. Tavernier, J.-M. Dumollard, D. Guyotat, M. Pe¤ oc’h. Toxoplasmosis with hemophagocytic syndrome after bone marrow transplantation: diagnosis at autopsy. Transpl Infect Dis 2008: 10: 372^374. All rights reserved

Reactivation of latent toxoplasmic infection is a well known disease in the immunocompromised hosts (1). In allogeneic hematopoietic stem cell transplantation (allo-HSCT), toxoplasmosis usually develops within the ¢rst 6 months after transplantation, with the highest incidence in the second and third months. In the absence of speci¢c treatment, this infection is associated with a fatal evolution (2). The diagnosis remains di⁄cult and misdiagnosis explains the high rate of mortality. In many reported cases, the diagnosis is only made at autopsy.

Case report A 59 -year-old man was admitted for acute myeloid leukemia with multilineage dysplasia. A complete remission

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S. Duband1,2, J. Cornillon3, E. Tavernier3, J.-M. Dumollard1,2, D. Guyotat3, M. Pe´oc’h1,2 1

Department of Pathology, Saint-Etienne University Hospital Center, Bellevue Hospital, St-Etienne, France, 2Research Unit JE 2521 ‘Biologie, Inge´nierie et Imagerie de la greffe de corne´e’, BiiGC, Jacques Lisfranc Faculty of Medicine, Jean Monnet University, Saint-Etienne, France, 3Department of Hematology, Saint-Etienne University Hospital Center, Bellevue Hospital, St-Etienne, France Key words: toxoplasmosis; autopsy; hemophagocytic syndrome; bone marrow transplantation Correspondence to: Sebastien Duband, Department of Pathology, Saint-Etienne University Hospital Center, Bellevue Hospital, 42055 St-Etienne, Cedex 2, France Tel: 33 (0) 04 77 12 05 23 Fax: 33 (0) 04 77 12 09 16 E-mail: [email protected] Received 15 October 2007, revised 11 January 2008, accepted for publication 6 February 2008 DOI: 10.1111/j.1399-3062.2008.00310.x Transpl Infect Dis 2008: 10: 372–374

was obtained with idarubicin and cytarabine. After consolidation with high-dose cytarabine, allogeneic peripheral stem cell transplantation with reduced-intensity conditioning was performed with an unrelated HLA-matched donor. At day 90, no acute graft-versus-host disease (GVHD) was noted and chimerism was mixed (o80% donor-type cells in blood). The immunosuppressive therapy (cyclosporine alone) was rapidly decreased. One month later, the patient presented with severe intestinal GVHD con¢rmed by biopsy. Immunosuppressive therapy was restarted with cyclosporine, mycophenolate mofetil, and corticosteroids. Initially, the GVHD resolved. After 5 months post transplant, jaundice associated with elevated liver enzymes and sub-febrile state (between 37.8 and 38.21C) appeared. A positive semi-quantitative polymerase chain reaction (PCR) analysis for cytomegalovirus DNA and antigenemia assay performed on blood specimens suggested a viral reactivation, and treatment with

Duband et al: Toxoplasmosis after BMT

ganciclovir was started. The patient’s condition deteriorated rapidly with weight gain due to di¡use subcutaneous edema. Chest and abdominal radiographs and ultrasonographic imaging showed bilateral pleural, pericardial, and peritoneal e¡usions without evidence of interstitial or alveolar pneumopathy. Based on these data, therapy for a venoocclusive disease was proposed with de¢brotide. F|nally, a general seizure occurred with impairment of consciousness 2 days before death from multiorgan failure, 21 days after a total duration of illness from onset of symptoms. Autopsy showed several disseminated necrotic areas in the right lenticular nucleus and in parietal, temporal, and occipital cortex, with a greenish appearance (F|g. 1). Histological examination of systematic tissue samples demonstrated numerous cysts of Toxoplasma gondii in brain (F|g. 1, in inset), and some in lung (F|g. 2a) and heart (F|g. 2b) and revealed signs of chronic and terminal cardiac failure with pulmonary edema and hepatic centrolobular congestion characterized by sinusoidal dilatation. Low numbers of cysts in heart and lungs and their small size without cystic membrane rupture suggested a recent dissemination, potentially implied in hemodynamic endstage. Bone marrow was in¢ltrated by activated macrophages phagocytizing blood cells as typically observed in hemophagocytic syndrome. The determination of antiT. gondii IgG antibody titer performed monthly during the post-transplant period showed a stable rate. Pre-transplant serologic tests (IgG antibody to T. gondii) were positive for the recipient and negative for the donor. However, retrospectively pre-mortem toxoplasmosis PCR was positive in blood. T. gondii, an obligate intracellular parasite, is endemic in a large part of Europe including France. After bone marrow transplant (BMT), 3 periods of infectious complica-

Fig. 1. Macroscopic appearance of brain injury consisting of hemorrhagic su¡usions in cortical layer of the left occipital lobe (arrow). Inset: toxoplasmic cysts (arrow) within a necrotic zone (HES,  1000).

Fig. 2. Histological aspect of lung (on the left, a) showing bronchial lumen (B), bronchial epithelial cell (BC), and toxoplasmic cyst (arrow) (HES staining, magni¢cation  1000). This bronchial location permits visualization of Toxoplasma gondii via bronchoalveolar lavage. On the right (b), the arrow indicates a cyst in a cardiomyocyte without surrounding in£ammatory in¢ltrate.

tions can be discerned. The pre-engraftment period is characterized by severe neutropenia associated frequently with mucosal damage, and bacterial infections are predominant. In the mid-recovery period, GVHD and its treatment contribute to diminished host defenses, leading essentially to viral and fungal infections. After 3 months, chronic GVH reaction impairs the monocyte macrophage function, reduces CD4 lymphocytes counts, and increases risks for infections with encapsulated bacteria, fungi, Pneumocystis jiroveci (carinii), and Toxoplasma (3). The incidence of reactivated toxoplasmosis has been calculated to be 2% in BMT recipients with a positive serostatus for toxoplasmosis before allo-HSCT (2, 4). The status of IgG antibody toT. gondii should be determined before the graft in order to identify patients with high risk of reactivation in the post-transplant period. Incidence of seropositivity in the general population was di¡erent and depends on regional epidemiology. Usually, the reactivation occurs within 6 months after allo-HSCT, as in our case, but later reactivations have already been described (5). Along with a positive serostatus pre-BMT, severe GVHD combined with intensi¢ed immunosuppressive treatment and negative serostatus of the donor are also well known risk factors for toxoplasma reactivation (6). Reactivation can be prevented by trimethoprim-sulfamethoxazole also used after BMT for P. jiroveci (carinii) pneumonia (PCP) prophylaxis. Our patient initially received this treatment, but it was stopped after a cutaneous rash and replaced by aerosol sprays of pentamidine, which is inactive for toxoplasmosis prevention. High fever is often the earliest sign of toxoplasmosis and should prompt diagnostic work up, especially in the

Transplant Infectious Disease 2008: 10: 372^374

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presence of risk factors. In our case, the sub-febrile state of the patient was probably a result of corticotherapy for GVHD masking a fever that otherwise would be higher. The other common presentation of toxoplasmosis in BMT patients is encephalitis. Pneumonitis and myocarditis are less frequent at presentation. Clinical signs of toxoplasma encephalitis are not speci¢c and include focal and generalized seizures, cognitive disturbances, headache, hemiparesis, ataxia, and impairment of consciousness (7 ). Ocular toxoplasmosis after HSCT, mostly occurring with disseminated infection, leads to necrotizing retinochoroiditis (5, 8). A PCR test forT. gondii in cerebrospinal £uid, bronchoalveolar lavage £uid, and peripheral blood samples is a very useful diagnostic tool. The functional consequences of toxoplasmosis of the heart vary considerably depending on the intensity of in£ammatory reaction, the extent of involvement of myocardial muscle ¢bers by necrosis, and intramyocytic presence of tachyzoites of T. gondii. Clinically, diagnosis of myocarditis remains a challenge because of the non-speci¢c pattern of clinical presentation. The spectrum of clinical presentation ranges from an asymptomatic state to fulminant condition causing sudden death, which sometimes can be confused with an infarct (9). Our patient developed chronic heart failure with anasarca and hepatic dysfunction without evidence of cardiac injury other than myocardial toxoplasmic dissemination. Toxoplasmic pneumonitis follows the same pathogenetic mechanism, but occurs less frequently than either toxoplasmic encephalitis or other opportunistic pneumonias, such as PCP. Clinical and radiographic ¢ndings in toxoplasmic pneumonitis are similar to those of PCP but the onset of disease tends to be more rapid (10). Diagnosis is based upon a high degree of clinical suspicion and demonstration of T. gondii in bronchoalveolar lavage £uid and/or lung biopsy specimens. In our case, pulmonary involvement noticed at autopsy was asymptomatic and the pulmonary edema is probably attributable to the ¢nal cardiac failure. In this report, clinical presentation was initially marked by hepatic injury without cardiac or pulmonary symptoms as described previously. Neurological manifestations occurred at end stage. The ¢nal cardiac failure could

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partially result from dissemination of the infection. The diagnosis of disseminated toxoplasmosis was made at necropsy. Blood PCR was not routinely performed after alloHSCT in our center. This case caused us to modify our protocol and we now perform surveillance blood PCR examination in seropositive patients with high immunosuppressive therapy and GVHD. Because of the numerous diseases that can occur after a BMTand their often atypical presentations due to immunode¢ciency we want to emphasize, through this case report, both the value of necropsy to establish a de¢nitive diagnosis and its medical educational role in improving patient care.

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